The glutamate hypothesis and the glutamate linked treatments of schizophrenia

1. 1 The Glutamate Hypothesis and the Glutamate Linked Treatments of Schizophrenia Dr Mohamed Abdelghani Ass. Lecturer Of Psychiatry Zagazig Faculty Of Medicine Available at : http :// www.slideshare.net/mabdelghani 9/28/2012

2. 2 Contents (I) The Glutamate System (II) Glutamate System and Schizophrenia a- NMDA Receptors Hypofunction Theory The Glutamate theory vs. the Dopamine theory in schizophrenia b- The Glutamate & Neurodevelopmental Theory c- The Glutamate & Neurodedegenarative Theory (III) Glutamate Linked Treatments of Schizophrenia 9/28/2012

3. 3 The Glutamate System L-Glutamate: “ the king of neurotransmission” 9/28/2012

4. 4 The Glutamate System: (Moghaddam, 2005) Glutamate is the major excitatory neurotransmitter in CNS (the king of neurotransmission). Nearly 50% of the neurons in the brain, esp. projecting from the cerebral cortex, use glutamate as their neurotransmitter. 9/28/2012

5. 5 Possible therapeutic applications (MRC Centre for Synaptic Plasticity 2010) Multifacet ischemia Epilepsy Parkinson's disease Alzheimer’s disease Hyperalgesia Diabetes Multiple Sclerosis Schizophrenia Anxiety Depression Others 9/28/2012

6. 6 Glutamate Receptors: (MRC Centre for Synaptic Plasticity 2010) Glutamate acts via two classes of receptors “in both neurones and glial cells” : Ligand gated ion channels ( Ionotropic receptors ): Four groups ( AMPA, NMDA, Kinate and Delta receptors). G-protein coupled ( Metabotropic receptors ). They are further broken down into three groups and eight subgroups: (mGlu1-mGlu8). 9/28/2012

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9. 9 Metabotropic Glutamate Receptors 9/28/2012

10. 10 (II) Glutamate system and schizophrenia NMDA Receptors Hypofunction Hypothesis of Schizophrenia The Glutamate theory vs. the Dopamine theory in schizophrenia The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of Schizophrenia The excessive pruning theory The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of Schizophrenia The excessive apoptosis theory 9/28/2012

11. (1) NMDA Receptors Hypofunction Hypothesis of Schizophrenia: The Glutamate theory vs. the Dopamine theory in schizophrenia 11 9/28/2012

12. 12 Glutamate system and schizophrenia The idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim and colleagues in 1980 ( Kim et al., 1980 ) based on their findings of low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia. 9/28/2012

13. 13 Glutamate system and schizophrenia Studies about Antiglutamatergic substances: Phencyclidine (PCP) or ketamine produces "schizophrenia-like" symptoms in healthy individuals and exacerbates pre-existing symptoms in patients with schizophrenia ( Javitt et al., 1991 ; Krystal et al., 1994 ; Lahti et al., 1995 ). 9/28/2012

14. 14 Glutamate system and schizophrenia Genetic studies: Most of genes that have recently been associated with an increased risk for schizophrenia can influence functions linked to glutamate receptors ( Harrison et al., 2003 ; Moghaddam , 2003 ). Postmortem receptors studies: Studies show changes in glutamate receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus of subjects with schizophrenia ( Clinton and Meador-Woodruff, 2004 ). 9/28/2012

15. 15 Glutamate system and schizophrenia Postmortem enzymes studies: Levels of amino acids N- acethylaspartate (NAA) and N- acethylaspartylglutamate (NAAG), and the activity of the enzyme that cleaves NAAG to NAA and glutamate are altered in the CSF and postmortem tissue from individuals with schizophrenia ( Tsai et al., 1995 ). Brain imaging studies: SPECT studies using a tracer for the NMDA receptor have reported reduced NMDA receptor binding in the hippocampus of medication-free patients ( Pilowsky et al., 2005 ) . 9/28/2012

16. The Glutamate theory vs. the Dopamine theory in schizophrenia 16 9/28/2012

17. 17 Key DA Pathways (a) The nigrostriatal pathway. (b) The mesolimbic pathway. (c) The mesocortical pathway (dorsolateral prefrontal cortex & ventromedial cortex). (d) The tuberoinfundibular pathway. (e) The thalamic DA pathway 9/28/2012

18. 18 The DA Hypothesis of Schizophrenia: Positive Symptoms 9/28/2012

19. 19 Dopamine Theory: the golden triad Drugs that increase dopamine, such as amphetamine and cocaine, can cause psychosis. Antidopaminergic drugs can  improve psychosis. Mechanism : overactivity in the mesolimbic dopamine pathway could be the mediator of positive symptoms of schizophrenia such as delusions and hallucinations. 9/28/2012

20. 20 The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms 9/28/2012

21. 21 Dopamine Theory: Problems It explains only part of schizophrenia (positive symptoms not negative symptoms). Anti- dopamenergic drugs usually: make negative symptoms worse in patients. induce negative symptoms in healthy people. Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better anti-schizophrenic drugs. 9/28/2012

22. 22 Dopamine Theory: problems cont. Under activity in  the meso -cortical dopamine pathway is hypothesized to be the mediator of negative symptoms of schizophrenia: This indicates that reduced dopamine activity is the problem rather than dopamine overactivity. DA theory is a “ psychosis theory ” more than it is a “schizophrenia theory”. 9/28/2012

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24. 24 Role of Glutamate in the Mesocortical System 9/28/2012

25. 25 Role of Glutamate in the Mesolimbic System 9/28/2012

26. 26 (2) The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of Schizophrenia The excessive pruning theory 9/28/2012

27. 27 Neurodevelopmental Theory of Schizophrenia (Fatemi & Folsom, 2009) Schizophrenia could be the result of an early brain insult, which affects brain development leading to abnormalities in the mature  brain (Murray et al, 1992). The theory has been postulated since Kraeplin in the early 20 th century. The cause of the brain lesion could be either: Abnormal genes, which impair brain development. Some foetal or neonatal adversity.  9/28/2012

28. 28 Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi & Folsom, 2009) Congenital Abnormalities: e.g. agenesis of corpus callosum, stenosis of sylvian aqueduct, cerebral hamartomas , low-set ears, epicanthal eye folds, etc. Environmental Factors: e.g. obstetric and perinatal complications, periventicular hemorrhages , hypoxia, and ischemic injuries and prenatal viral infections. Biological markers : e.g. changes in the proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis. 9/28/2012

29. 29 Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi & Folsom, 2009) Genetics studies: e.g. various genes, involved in schizophrenia, were also involved in signal transduction, cell growth and migration, myelination, regulation of presynaptic membrane function, and GABAergic function. Brain Pathology: e.g. cortical atrophy, ventricular enlargement, reduced volume of various brain parts, abnormal laminar organization and orientation of neurons, decreased cellularity and cerebellar atrophy 9/28/2012

30. 30 Neurodevelopmental Theory of Schizophrenia (Gupta & Kulhara, 2010) During adolescence, brain changes normally include: Decrease in delta sleep Decrease in membrane synthesis Decreased volume of cortical gray matter Decreased prefrontal metabolism In schizophrenia, there are more pronounced decrements in the same parameters. Feinberg (1983): t his supports the possibility of an exaggeration of the normal process of synaptic pruning that occurs in schizophrenia during adolescence . 9/28/2012

31. 31 Neurodevelopmental Theory of Schizophrenia: Models ( Corroon, 2005 ) The early neurodevelopmental model: fixed lesion from early life interacts with normal neurodevelopment occurring later, lying dormant until the brain matures sufficiently to call into operation the damaged systems (Murray & Lewis, 1987). The late neurodevelopmental model: schizophrenia may result from an abnormality in peri-adolescent synaptic pruning ( Feinberg, 1983 ). 9/28/2012

32. 32 Neurodevelopmental Theory of Schizophrenia: “2-hit” model (Fatemi & Folsom, 2009) Keshavan and Hogarty (1999): maldevelopment in schizophrenia takes place during 2 critical time points (early brain development and adolescence): Early developmental insults may lead to dysfunction of specific neural networks that would account for premorbid signs At adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms. 9/28/2012

33. 33 Glutmate and Neurodevelopmental Theory of Schizophrenia NMDA receptors are a critical component of developmental processes during adolescence ( Moghaddam , 2005). This includes: development of neural pathways Neural migration Neural survival Neural plasticity Neural pruning of cortical connections 9/28/2012

34. 34 Glutmate and Neurodevelopmental Theory of Schizophrenia Stahl (2009): suggests that Glutamate excitotoxicity first facilitates the neurodevelopmental disorder in adolescence. Later, this results in a chronic state of Glutamate hypofunctioning which maintains the schizophrenic pathology in later stages. 9/28/2012

35. 35 (3) The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of Schizophrenia The excessive apoptosis theory 9/28/2012

36. Glutamate and Neurodegenerative Model of Schizophrenia (Woods, 1998) Kraeplin and others believed that Schizophrenia is caused by a form of progressive neuronal degeneration characterized by earlier onset than that seen with previously described entities, such as Huntington's disease or Alzheimer's disease > Dementia praecox However, the neurodegenerative theory was opposed by the neurodevelopmental theory : Most of the brain pathology in schizophrenia starts in early adulthood No evidence of necrosis There is no neurochemical explanation for neurodegeneration Theory was later supported by the discoveries about apoptosis and glutamate system. 36 9/28/2012

37. 37 Glutamate and Neurodegenerative Model of Schizophrenia (Glantz et al, 2006; Jarskog et al, 2005) The neurostructural changes in schizophrenia have led to the hypothesis that apoptosis (programmed cell death) may contribute to the pathophysiology of schizophrenia. Such changes include: Reduced neuropils ( region between neuronal cell bodies in the gray matter ) and reductions of neurons. Neuroimaging data > progressive loss of cortical grey matter in schizophrenia . Postmortem studies: markers of apoptosis and levels of apoptotic proteins indicate > increased apoptotic vulnerability. 9/28/2012

38. 38 Glutamate and Neurodegenerative Model of Schizophrenia Again , glutamate is the main factor involved in apoptosis (Stahl, 2009) : High concentrations of glutamate accumulate in the brain are thought to be involved in the aetiology of a number of neurodegenerative disorders including Alzheimer's disease (Coyle & Puttfarcken , 1993; Lipton & Rosenberg, 1994;). A number of invitro studies > at high concentrations, glutamate is a potent neurotoxin capable of destroying neurons by apoptosis ( Behl et al. 1995; Zhang & Bhavnani , 2003). 9/28/2012

39. 39 9/28/2012 Mg2+ Glutamate Calcium AMPA* receptor Presynaptic neurone Postsynaptic neurone NMDA receptor Na + [Ca 2+ ]

40. 40 Conclusion of Glutmate role in Schizophrenia Both glutamate hypo activity as well as hyper activity contribute to the pathology of schizophrenia (Stahl, 2009). Gupta & Kulhara (2010) suggested that: Schizophrenia cannot be explained by a single process of development or degeneration. Research evidence exists for degeneration as well as developmental disorders. The glutamatergic hypothesis bridges the gap between development and neurodegeneration in schizophrenia > "three hit hypothesis" (Keshavan, 1999). 9/28/2012

41. 41 Clinical and pathological stages of schizophrenia (Gupta & Kulhara, 2010)                                                                                                                                                                                                                                    9/28/2012

42. 42 Glutamate Linked Treatments of Schizophrenia 9/28/2012

43. 43 Glutamate Linked Treatments of Schizophrenia: Three classes of medications: NMDA partial antagonists (early stage schizophrenia) NMDA partial agonists (later stage schizophrenia): Glycine co-agonists Glycine transporters inhibitors NMDA modulators mGlu autoreceptors co-agonists Minocycline 9/28/2012

44. 44 (1) NMDA Partial Antagonists : (Stahl, 2009) To treat excitotoxicity in early stage. They include : PCP and Ketamine: highly schizophrenogenic NMDA partial antagonists e.g. memantine (already used in Alzheimer) Drugs which block presynaptic release of glutamate e.g. Lamotrigine , gabapentin and pregabalin . Anti-free radicals drugs e.g. vitamin E and experimental agents called lazaroids (so-named because they purport to raise neurons from the dead, like the biblical Lazarus). 9/28/2012

45. 45 (2) NMDA Partial Agonists “ Glycine co-agonists” To treat glutamate hypofunctioning in later stages of schiz . They act as agonists at the allosteric glycine receptor site of the NMDA complex (glycine co-agonists) as a way to avoid causing glutamate neurotoxicity Chaves et al. (2009 ) . Two ways to this: 9/28/2012

46. 46 Glycine agonists to activate glycine site on the NMDA receptors as indirect way to potentiate the glutamte effect. e.g. glycine, d-serine, d-alanine and d- cycloserine . Provisional studies are promising. Research is still going on, using stronger agonists. Glycine transporters inhibitors (GlyT1 inhibitirs ): e.g. sarcosine > promising remedy for negative symptoms of schizophrenia ( Chaves et al, 2009) (Stahl, 2009 ). 9/28/2012

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48. 48 (3) NMDA Modulators mGlu autoreceptors co-agonists Wieronska and Pilc (2009): mGlu receptors are the ideal target for medication (co-agonists) e.g. methionine amide. Mechanisms of action are not quite clear. mGluR2/3 are mainly autoreceptors that prevent glutamate release. The final result is enhancing glutamate activity (?????). 9/28/2012

49. 49 NMDA Modulators: mGlu2/3 autoreceptors co-agonists They reverse the effects of PCP and Ketamine in animals (Stahl, 2009) Some studies > methionine amide: effective against + ve and - ve symptoms of schizophrenia (Moghaddam, 2005). A RCT > after four weeks of treatment, an agonist for the mGluR2/3 (LY404039 ) has similar efficacy as Olanzapine in ameliorating positive and negative symptoms of schizophrenia ( Patil et al., 2007 ). 9/28/2012

50. 50 NMDA Modulators: Minocycline (Chaves et al, 2009) Second-generation tetracycline with a broad spectrum of antimicrobial activities and anti-inflammatory properties Latest studies suggest that it is related to the glutamatergic system: minocycline reversed several NMDA antagonist effects in animal studies and showed good results in the treatment of patients with schizophrenia Has neuroprotective effects in several animal and human models of neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and ischemia 9/28/2012

51. 51 9/28/2012 ( Ellenbroek , 2012)

52. 52 Comments Glutamate hypothesis is a welcome addition but it is not well developed yet, many issues need clarification : Interactions between glutamate system, glycine system, monoamines and other systems. Glutamate linked drugs would be used in treatment of schizophrenia with possible effects on depression, anxiety, epilepsy, etc Glutamate excitotoxicity and NMDA hypofunctioning in schizophrenia is not clear. Why mGlu2/3R agonists can enhance glutamate activities despite of the fact that they should be reducing the release of glutamate?????? 9/28/2012

53. 53 Comments We need to avoid the dopamine mistake: Could it be over simplistic to attribute a major illness to the mere quantitative increase or decrease of one chemical transmitter? Could it be over simplistic to assume that schizophrenia is a one illness with a one neurochemical pathology. Is possible that glutamate theory is a theory of something else e.g. neuronal excitability rather than schizophrenia theory. This would be similar to the argument that dopamine theory is a theory of psychosis not of schizophrenia? 9/28/2012

54. 54 Thank U 9/28/2012